1-substituted-3-aroyl-pyrrolidines



United States Patent 3,489,769 1-SUBSTlTUTED-3AROYL-PYRROLIDINES GroverCleveland Helsley and William John Welstead,

Jr., Richmond, Va., assignors to A. H. Robins Company, Incorporated,Richmond, Va., a corporation of Virginia No Drawing. Continuation-impartof application Ser. No. 570,722, Aug. 8, 1966. This application June 20,1968, Ser. No. 738,414

Int. Cl. C07d 27/06 US. Cl. 260-326.5 16 Claims ABSTRACT OF THEDISCLOSURE The present invention describes l-substituted3-aroylpyrrolidines which have been shown to be useful in loweringplasma cholesterol levels. The compounds are prepared froml-substituted-3cyanopyrrolidines by reaction with aryl magnesiumhalides.

Formula I wherein:

R is hydrogen, lower alkyl, aryllower-alkyl, aryloxy,

ethoxy, aroyl, lower cycloalkyl, carbethoxy, and w-alkoxyalkyl,

R is hydrogen, lower alkoxy, trifluoromethyl, halogen having an atomicweight less than 80, and lower alkyl, and acid addition salts thereof.

The compounds of the invention having the foregoing Formula I aregenerally characterized by important pharmacological activity and areeifective as hypocholesterolemic agents and, as such, are particularlyuseful in lowering plasma cholesterol levels in living animal bodies asdemonstrated in rats. Male rats of the Sprague-Dawley strain, weighingbetween 150200 grams, were placed in individual cages with raised wirefloors and subjected to a 12-hour day with artificial lighting in a roomcontrolled at 7578 F. The rats remained under these conditions for fourdays prior to experimentation to adjust to their environment. They werefed a semi-purified basal diet containing 0.375% by weight of thecompound being investigated. On the fifth day the rats were randomlyselected and divided into two groups. At the end of 21 days and after anovernight fast, the rats were anesthetized with ether and terminallybled from the dorsal aorta into heparinized tubes (Proc. Animal CarePanel 11, 305, 1961). Plasma was extracted according to Dole andMeinertz (J. Biol. Chem. 235, 2995, 1960), and lipids were resolved on asilicic acid column (I. Am. Oil. Chem. Soc. 36, 294, 1959) and totalcholesterol (Am. J. Clin. Path. 27, 583, 1957) was analyzed (Clin. Chem.7, 249, 1961). Among the novel compounds of the present invention thepreferred compound is Example No. 5, 1-(2-ethoxyethyl)3-(4-fluorobenzoyl)pyrrolidine. When test- 3,489,769Patented Jan. 13, 1970 ed as described hereinabove, the plasmacholesterol level in rats was lowered approximately 50%. The 50%lowering of plasma chloresterol is comparable to that obtained when theknown cholesterol lowering agent, ethyl2-(pchlorophenoxy)2-methylpropionate (Atromid-S was used as a controldrug in the procedure described hereinabove.

It is, accordingly, an object of the present invention to provide newand useful l-substituted-3-aroyl pyrrolidines and methods of making thesame. Other objects of the invention will be apparent to one skilled inthe art, and still others will become apparent hereinafter.

In the definition of the symbols in the foregoing Formula I and wherethey appear elsewhere throughout this specification the terms have thefollowing significance.

The term lower alkyl as used herein includes straight and branched chainradicals of up to eight carbon atoms inclusive, preferably no more thansix carbon atoms, and is exemplified by such groups as methyl, ethyl,propyl, isopropyl, butyl, sec. butyl, tertiary butyl, amyl, isoamyl,hexyl, heptyl, octyl and the like. A lower-alkoxy group has the formulaO-lower-alkyl.

The term lower cycloalkyl as used herein includes primarily cyclicradicals containing three up to nine carbon atoms inclusive andencompasses such groups as cyclopropyl, cyclobutyl, cyclohexyl,cyclopentyl, methylcyclohexyl, propylcyclohexyl, ethylcyclopentyl,propylcyclopentyl, dimethylcyclohexyl, cycloheptyl, and cyclooctyl.

The term lower alkylene has the formula (CH wherein m is a positiveinteger from l-4 inclusive.

Included in the term aryllower-alkyl are lower-alkyl substituted phenylgroups such as benzyl, phenethyl, methylbenzyl, phenpropyl and the like.

An aryl radical refers to the. phenyl radical alone or to a phenylradical substituted by any radical or radicals which are not reactive orotherwise interfering under the conditions of reaction, such radicalsincluding lower alkoxy, lower alkyl, trifiuoromethyl, halo and the like.The aryl radicals have preferably no more than one to three substituentssuch as those given above and, furthermore, these substituents can be invarious available positions of the aryl nucleus and, when more than onesubstituent is present, can be the same or different and can be invarious position combinations relative to each other.

An aroyl radical has the formula An aryloxy radical has the formulaO-aryl.

This invention also includes acid addition salts of the above definedbases formed with nontoxic organic and inorganic acids. Such salts areeasily prepared by methods known in the art. When the compounds are tobe used as intermediates for preparing other compounds or for any othernon-pharmaceutical use, the toxicity or nontoxicity of the salt isimmaterial; when the compounds are to be used as pharmaceuticals, theyare most conveniently used in the form of nontoxic acid-addition salts.Both toxic and nontoxic salts are therefore within the purview of theinvention. The acids which can 'be used to prepare the preferrednontoxic acid-addition salts are those which produce, when combined withthe free bases, salts whose anions are relatively innocuous to theanimal organism in therapeutic doses of the salts, so that beneficialphysiological properties inherent in the free bases are not vitiated byside effects ascribable to the anions.

The base is reacted with the calculated amount of organic or inorganicacid in aqueous miscible solvent, such as ethanol or isopropanol, withisolation of the salt by concentration and cooling, or the base isreacted with an excess of the acid in aqueous immiscible solvent, suchas ethyl ether or isopropyl ether, with the desired salt separatingdirectly. Exemplary of such organic salts are those formed withmaleicQ-fumaric, benzoic, ascorbic, pamoic, succinic, methanesulfonic,acetic, propionic, tartaric, citric, lactic, malic, citraconic,itaconic, hexamic, p-arninobenzoic, glutamic, stearic acid and the like.Exemplary of such inorganic salts are those formed with hydrochloric,hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids.

The novel compounds of this invention as represented by Formula I areprepared from 1-R-3-cyanopyrrolidines prepared as described in US.Patent 3,318,908. Thus a l-R-3-cyanopyrrolidine of Formula II, wherein Ris lower alkyl, lower cycloalkyl, aryl and phenyllower-alkyl is reactedin a dry inert organic solvent, preferably ether, with an arylmagnesiumhalide to give a 1-R-3-aroylpyrrolidine of Formula III, wherein R is asdefined immediately hereinabove.

Of particular value is the compound of Formula II, wherein R isphenylloWer-alkyl as represented by the benzyl group. The1-benzyl-3-aroylpyrrolidine of Formula III prepared from1-benzyl-3-cyanopyrrolidine and an arylmagnesium halide is reacted withan excess of cyanogen bromide in a dry inert organic solvent,illustratively chloroform, to give a 1-cyano-3-aroylpyrrolidine whichgenerally is not isolated, and is hydrolyzed with dilute hydrochloricacid for a period of from about 12 hours to about 16 hours to give a1-carbamoyl-3-aroylpyrrolidine. The latter compound is furtherhydrolyzed with concentrated hydrochloric acid for a periodof from 48hours to about 72 hours to give a 3-aroylpyrrolidine. Alternately, theresidual crude material remaining after evaporation of the chloroformsolvent following the reaction described above with cyanogen bromide canbe hydrolyzed directly to the 3-aroylpyrrolidine using concentratedhydrochloric acid.

3-aroylpyrrolidines can also be prepared by another method as follows:

(1) An w-dialkylamino propionphenone is reacted with aziridine, theaziridine moiety displacing the dialkylamino group to give anw-aziridinylpropiophenone of Formula IV.

(2) The w-aziridinylpropiophenone of Formula IV is treated in a dryinert solvent below 20 C. with ethyl chlorocarbonate to give anw-[N-carbethoxy-N-(Z-chloroethyl)amino]-propiophenone of Formula V.

H2 Formula IV COOC H CHgCHzCl Formula V C 0 00 115 Formula VI (4) The1-carbethoxy-3-aroylpyrrolidine of Formula VI is hydrolyzed under acidicconditions to a 3-aroylpyrrolidine.

The 3-aroylpyrrolidines prepared by the methods described hereinaboveconstitute novel compounds of Formula I which are especially useful inpreparing other novel and useful compounds within the scope of FormulaI. Thus, the hydrogen atom of the secondary amine group of thepyrrolidine nucleus exhibits all the reactive properties of a secondaryamino group and enters readily into conventional displacement reactionswith a variety of reactive compounds, including, for example, alkylhalides, aralkyl halides, N-mono and N,N-disubstituted carbamoylhalides, arylsulfonyl halides, and the like.

Generally speaking, the 3-aroylpyrrolidines prepared as described aboveare reacted with compounds containing reactive halogen atoms in a loweralkanol solvent, illustratively ethanol, containing an alkali metal saltas, for example, sodium carbonate as an acid binder. The reaction ispreferably carried out at the reflux temperature of the solventemployed, and following the reaction period the product is extractedinto an organic solvent, preferably ether, by acid-base extraction ofthe concentrated residue of the reaction mixture. After washing anddrying, the solvent is evaporated and the product present in the residueis purified by conventional laboratory procedures as, for example,distillation, crystalllization, chromatography, and the like.

For specific insight into the type of reactions involved, theintermediates therefor and the manner of carrying them out, and thenovel compounds, some of these are specifically set forth in a series ofspecific examples which follow. It is to be understood the examples aregiven by way of illustration only and are not to be construed aslimiting.

EXAMPLE 1 3-benzoyl-l-ethylpyrrolidine An ethereal solution ofphenylmagnesium bromide was prepared using 61 g. (2.5 mole) ofmagnesium, 41 0 g. (2.6 mole) of bromobenzene and 650 ml. of dry ether.The stirred ethereal solution was treated with 248 g. (2.0 mole) ofB-cyano-l-ethylpyrrolidine dissolved in an equal volume of dry ether andfollowing addition the mixture was refluxed six hours. The reactionmixture was decomposed by the careful addition of a solution of 250 g.of ammonium chloride in 750 ml. of water. Following evaporation of theether, the solution was heated on the steam bath to complete hydrolysisof the ketimine. The product was extracted with ether and then separatedfrom nonbasic materials by acid-base extraction. The residual oil wasdistilled at 97-99 C./.05 mm. to give 180 g. (44%) of3-benzoyl-l-ethylpyrrolidine.

Using the process given above in Example 1, the following compounds areprepared from the stated ingredients:

3-benzoyl-l-cyclohexylpyrrolidine is prepared froml-cyclohexyl-3-cyanopyrrolidine and phenylmagnesium bromide,

3-benzoyl-l-cyclopentylpyrrolidine is prepared froml-cyclopentyl-3-cyanopyrrolidine and phenylmagnesium bromide,

1 cyclohexyl 3 (m tritiuoromethylbenzoyl) pyrrolidine is prepared from1-cyclohexyl-3-cyanopyrrolidine and m-trifluoromethylphenylmagnesiumbromide.

EXAMPLE 2 3-benzoyl-1-rnethylpyrrolidine To a stirred ether solution ofphenylmagnesium bromide prepared from 37.5 g. (1.55 mole) of magnesium,251 g. (1.60 mole) of bromobenzene and 425 ml. of dry ether was addeddropwise a solution of g. (1.27 mole) of 3-cyano-l-methylpyrrolidine in200 ml. of dry ether. After refluxing two hours, the cooled reactionmixture was treated with a solution of 80 g. of ammonium chloride in 260ml. of water. The ether was evaporated, the aqueous solution heated onehour to complete hydrolysis of the ketimine and the ketone productextracted with ether. Non-basic materials were separated by acid-baseextraction. The residual oil after removal of the ether solvent wasdistilled in vacuo to give 102 g. (41%) of product at 93-95 C./.05 mm.

Analysis.Calculated for C H NO: N, 7.40. Found: N, 7.57.

EXAMPLE 3 3-benzoyl-l-isopropylpyrrolidine fumarate To a stirredsolution of 2 moles of phenyl magnesium bromide in one liter of etherwas added slowly 202 g. (1.46 mole) of 3-cyano-l-isopropylpyrrolidine in200 ml. of dry ether. After the addition was complete the mixture wasstirred and refluxed for three hours and then allowed to standovernight. To the cooled suspension was then added slowly with stirring250 g. of ammonium chloride in 750 ml. of water. After the ether wasevaporated, the mixture was heated for one hour on a steam bath toinsure hydrolysis of ketimine. The ketone was extracted with ether andthe combined ether extracts were extracted with 6 N HCl. The acidextracts were made basic with 50% NaOH and the free base was taken upwith ether. The ether extracts were washed with water and dried overmagnesium sulfate. After the solvent was evaporated, the residual oilwas distilled at reduced pressure and the fraction boiling at 98100C./.003 mm. was collected. The light yellow, non-viscous oil weighed 120g. (38% yield). To a warm solution of 3.7 g. (0.032 mole) of fumaricacid in 150 ml. of isopropanol was added 7.0 g. (0.032 mole) of the freebase. The fumarate salt was collected and dried (8.5 g.; M.P. 122125C.). After recrystallization from isopropanol the dried fumarate salt(5.0 g.) melted at 125-127 C.

Analysis.-Calculated for C H NO C, 64.85; H, 6.95; N, 4.20. Found: C,65.16; H, 6.96; N, 4.05.

EXAMPLE 4 1-methyl-3-(m-methoxybenzoyl)-pyrrolidine To a stirredGrignard solution prepared from 14.6 g. (0.60 mole) of magnesium, 112 g.(0.60 mole) of m-bromoanisole in 250 ml. of ether was added slowly at arate which maintained gentle refluxing a solution of 60.5 g. (0.55 mole)of 1-methyl-3-cyanopyrrolidine in 50 ml. of dry ether. Stirring wascontinued for one hour after the addition was complete. To the cooledmixture was then added slowly a solution of 32 g. (0.60 mole) ofammonium chloride in 400 ml. of water. The ether layer was evaporatedand the resulting aqueous suspension was heated for one hour on a steambath to insure hydrolysis of the ketimine. The ketone was extracted withbenzene and the combined extracts were extracted with 6 N HCl. After theacid extracts were made basic with 6 N NaOH, the free base was taken upin benzene. The benzene extracts were washed with water and dried overmagnesium sulfate. After the solvent was evaporated, the residual oilwas distilled at reduced pressure and the fraction boiling at l2ll24 C./.07 mm. was collected. The light yellow, non-viscous oil weighed 30.8 g.(25% yield).

Analysis.Calculated for C H NO C, 71.20; H, 7.82; N, 6.39. Found: C,70.60; H, 7.89; N, 6.41.

EXAMPLE 5 1- (2-ethoxyethyl) -3- (p-fluorobenzoyl -pyrrolidine oxalateTo a stirred Grignard solution prepared from 11.2 g. (0.46 mole) ofmagnesium, 80.5 g. (0.46 mole) of pbrornofluorobenzene in 300 ml. ofether was added slowly at a rate which maintained gentle refluxing asolution of 44 g. (0.26 mole) of 1-(2-ethoxyethyl)-3-cyanopyrrolidine in60 ml. of dry ether. Stirring was continued for one hour after theaddition was complete. To the cooled mixture was added slowly a solutionof 26.8 g. (0.50 mole) of ammonium chloride in 300 m1. of water. Theether layer was evaporated and the aqueous suspension heated for an houron a steam bath to insure hydrolysis of the ketimine. The ketone wasextracted with ether and the combined extracts were extracted with 6 NHCl. After the acid extracts were made basic with 6 N NaOH the free basewhich separated was taken up in ether. The ether extracts were washedwith water and dried over magnesium sulfate. After the solvent wasevaporated, the residual oil was distilled at reduced pressure and thefraction boiling at ISO-133 C./0.07 mm. was collected. The light yellow,non-viscous oil weighed 12.9 g. (19% yield). The free base (12.0 g.;0.044 mole) was added to a solution of 5.6 g. (0.044 mole) of oxalicacid dihydrate in hot isopropanol. The mixture was heated severalminutes, filtered and cooled. The crystalline product which separatedmelted at 14l142 C. and weighed 12.2 g.

EXAMPLE 6 1-benzyl-3-benzoylpyrrolidine hydrochloride hydrate To astirred solution of 544 g. (3.0 mole) of phenylmagnesium bromide in 1.5liters of dry ether was added 279 g. (1.5 mole) of1-benzyl-3-cyanopyrrolidine in 400 ml. of dry ether at a rate whichmaintained gentle refluxing. The mixture was stirred for two hours atroom temperature after the addition was complete, cooled and treatedwith 151 g. (3.0 mole) of ammonium chloride in 900 ml. of water. Afterthe ether was evaporated the aqueous suspension was heated on a steambath for several hours to insure hydrolysis of the ketimine. The mixturewas then extracted with ether and the combined extracts were washed withwater and dried over magnesium sulfate. The solvent was evaporated andthe residual oil distilled at reduced pressure. The light yellow oilboiling at 172175 C./.08 mm. weighed 210 g. (53% yield). A portion ofthe free base (6 g.) was treated with 3 N HCl and the white crystallinehydrochloride which formed was recrystallized from water. The saltweighed 2.6 g. and melted at 116118.5 C.

Analysis.Calculated for C H NO Cl: C, 67.59; H, 6.93; N, 4.38. Found: C,67.85; H, 6.94; N, 4.42.

EXAMPLE 7 1-benzyl-3 (m-trifluoromethylbenzoyl) -pyrrolidinehydrochloride To a stirred Grignard solution prepared from 32.4 g. (1.3mole) of magnesium, 300 g. (1.3 mole) of m-bromobenzotrifluoride in 450ml. of ether was added 186 g. (1.0 mole) of 1-benzyl-3-cyanopyrrolidinein 200 ml. of dry ether at a rate which maintained gentle refluxing. Themixture was stirred at reflux for one hour, cooled and treated with asolution of 70 g. (1.3 mole) of ammonium chloride in 600 ml. of water.After the ether was evaporated, the mixture was heated for one hour on asteam bath to insure hydrolysis of the ketimine. The mixture wasextracted with ether and the combined extracts were washed with water,dried over magnesium sulfate and the solvent evaporated. The residualoil was distilled at reduced pressure and the fraction boiling at l67C./.07 mm. collected. The light yellow oil weighed 123 g. (37% yield). Aportion (23 g.) of the product was redistilled slowly and the fractionboiling at 148-150 C./.04 mm. collected. The oil weighed 16 g. A portion(10 g.) of the oil was dissolved in ether and treated with etherealhydrogen chloride. The white hydrochloride which formed melted at 158160 C. and weighed 9.8 g. after it was recrystallized from methyl ethylketone.

Analysis.-Calculated for C H NOClF C, 61.70; H, 5.18; N, 3.79. Found: C,61.75; H, 5.15; N, 3.99.

7 EXAMPLE 8 1-benzy1-3-(p-fluorobenzoyl)-pyrrolidine hydrochloride Tothe stirred Grignard solution prepared from 42.5 g. (1.76 mole) ofmagnesium, 308 g. (1.76 mole) of fluorobromobenzene in 700 ml. of etherwas added 164 g. (0.88 mole) of 1-benzyl-3-cyanopyrrolidine in 100 ml.of dry ether at a rate which maintained gentle refluxing. The mixturewas stirred for one hour at ambient temperature, cooled and treated witha solution of 94 g. (1.8 mole) of ammonium chloride in 500 ml. of water.The resulting suspension was stirred and heated on a stream bath for 16hours, cooled and treated with 500 g. of 50% NaOH. Toluene was added tothe flask and the mixture was heated for one hour on a steam bath toinsure hydrolysis of the ketimine. The suspension was filtered and thecake washed with toluene. The organic layer was separated, washed withwater and dried over magnesium sulfate. The solvent was evaporated andthe residual oil was distilled at reduced pressure. The fraction boilingat 169-170 C./.05 mm. weighed 103 g. (41% yield). A portion of the freebase (7.6 g.) was dissolved in isopropyl ether and treatedwith etherealhydrogen chloride. The salt weighed 5.3 g. and melted at 163165 C. afterit was recrystallized from an isopropanol-isopropyl ether mixture.

Analysis.Calculated for C H ClFNO: C, 67.60; H, 5.99; N, 4.38. Found: C,67.82; H, 5.95; N, 4.54.

EXAMPLE 9 3-benzoyl-l-carbamoylpyrrolidine To a stirred solution of 68.8g. (0.65 mole) of cyanogen bromide in one liter of chloroform was added148 g. (0.56 mole) of l-benzyl-3-benzoylpyrrolidine in 200 ml. ofchloroform over a period of five hours. After the addition was complete,the solution was refluxed for one hour and then the solvent wasevaporated at reduced pressure. The residual oil was treated with 1600ml. of 4 N HCl and refluxed for 16 hours. The mixture was cooled andextracted with ether. The aqueous layer was treated with NaOH and thenextracted with chloroform. The chloroform was evaporated and theresidual oil which crystallize-d on cooling was recrystallized fromethyl acetate using charcoal. The product weighed 57 g. (58% yield). Thematerial melted at 127.5128.5 C. after it was recrystallized from theethyl acetate.

Analysis.Calculated for C H N O C, 66.03; H, 6.46; N, 12.83. Found: C,65.83; H, 6. 48; N, 12.71.

EXAMPLE 1-carbamoyl-3 (p-fluo robenzoyl -pyrrolidine To a stirredsolution of 44.6 g. (0.43 mole) of cyanogen bromide in 400 ml. ofchloroform was added 95 g. (0.33 mole) of1-benzyl-3-(p-fluorobenzoyl)-pyrrolidine in 100 ml. of chloroform over aperiod of five hours. After the addition was complete, the solution wasrefluxed for 1.5 hours and then the solvent was evaporated at reducedpressure. The residual oil was treated with 1600 ml. of 4 N HCl andrefluxed for 16 hours. The mixture was cooled and extracted with ether.The aqueous layer was made basic with NaOH and then extracted withchloroform. The chloroform was evaporated in the residual oilcrystallized on cooling. The crystalline product weighed 32 g. (41%yield) after it was triturated with ethyl acetate and dried. The productwas recrystallized from ethyl acetate-ethanol and the white crystallinematerial melted at 136.5137.5 C.

Analysis.Calculated for C H FN O C, 61.01; H, 5.54; N, 11.86. Found: C,61.09; H, 5.41; N, 11.61.

EXAMPLE l1 3-(m-trifluoromethylbenzoyl)-pyrrolidine oxalate To a stirredsolution of 44.6 g. (0.043 mole) of cyanogen bromide in 400 ml. ofchloroform was added over a period of four hours, 102 g. (0.31 mole) of1-benzyl-3 (rn-trifiuoromethylbenzoyl)-pyrrolidine. After the additionwas complete, the mixture was heated at reflux for one hour and then thesolvent was evaporated at reduced pressure. An acidic solution of theresidual oil in 1200 ml. of 3 N hydrochloric acid was refluxed for 24hours. The cooled acidic solution was decanted from a dark viscousresidue and made basic with 25% sodium hydroxide and the basic solutionextracted with benzene. The combined extracts were washed with water,dried over magnesium sulfate and the solvent evaporated. A solution ofthe residual oil (24 g., 0.1 mole) in isopropyl ether was treated with asolution of 12.6 g. (0.10 mole) of oxalic acid dihydrate in methanol.The crude salt which formed was recrystallized from isopropanol yielding7.0 g. (7% yield) of product melting at 86-87 C.

Analysis.Calculated for C H F NO C, 50.45; H, 4.23; N, 4.20. Found: C,50.33; H, 4.29; N, 4.47.

EXAMPLE l2 3-benzoylpyrrolidine hydrochloride hydrate A solution of 18g. of 3-benzoyl-l-carbamoylpyrrolidine in 120 ml. of concentrated HClwas refluxed three days, cooled and made basic with 50% NaOH. The oilwhich separated was extracted with benzene and the combined extractswere washed with water, dried over magnesium sulfate and the solventevaporated. The residual oil weighed 8.1 g. (53% yield). A portion ofthe free base (5.0 g.) was dissolved in isopropanol and treated withethereal HCl. The salt which formed was recrystallized from anisopropanol-ether mixture. The product weighed 2.5 g. and melted at 5961C.

Analysis.--Calculated for C H NO CI: C, 57.51; H, 7.02; N, 6.10. Found:C, 57.73; H, 6.80; N, 6.22.

EXAMPLE 13 3- (p-fiuorobenzoyl -pyrrolidine oxalate A mixture of 50 g.of 1-carbamoyl-3-(p-fluorobenzoyl)-pyrrolidine in 400 ml. of cone. HClwas refluxed three days, cooled and made basic with 50% NaOH. The oilwhich separated was extracted with benzene and the combined extractswere washed with water, dried over magnesium sulfate and the solventevaporated. The residual oil weighed 19.0 g. (46% yield). A portion (1.9g., 0.01 mole) of the free base was dissolved in isopropanol and treatedwith 1.3 g. (0.01 mole) of oxalic acid dihydrate and heated severalminutes. The crystalline salt which separated on cooling wasrecrystallized again from the same solvent. The salt weighed 1.8 g. andmelted at 116119 C. (rapid heating). When the salt was heated slowly itsoftened at 115-117 C. and melted at 120- 124 C.

AnaZysis.-Calculated for C H FNO C, 55.12; H, 4.98; N, 4.95. Found: C,55.40; H, 5.01; N, 4.99.

EXAMPLE 14 1- [3-(p-acetyl-o-methoxyphenoxy propyl] -3-(p-fluorobenzoyl)-pyrrolidine oxalate A stirred mixture of 4.8 g. (0.025mole) of 3-(p fluorobenzoyl)-pyrrolidine, 7.8 g. (0.027 mole) of3-(pacetyl-o-methoxyphenoxy)-propyl bromide, 14 g. of potassiumcarbonate and 100 ml. of l-butanol was heated at -80 C. for 16 hours,cooled, filtered and the solvent evaporated. The residual oil was takenup in benzene and washed with water. After the solution was dried overmagnesium sulfate, the solvent was evaporated. The residual oil wasdissolved in isopropanol and treated with 3.2 g. (0.025 mole) of oxalicacid dihydrate, heated for several minutes and the resulting solutionfiltered. The salt which crystallized on cooling weighed 7.1 g. (61%yield) and melted at -103 C.

Analysis.Calculated for C H FNO C, 61.34; H, 5.77; N, 2.86. Found: C,61.86; H, 5.79; N, 2.86.

9 EXAMPLE 1-[2-(p-acetyl-o-methoxyphenoxy) -ethyl] -3-benzoylpyrrolidine oxalate A stirred mixture of 3.5 g. (0.02 mole) of3-benzoy1- pyrrolidine, 5.5 g. (0.02 mole)Z-(p-acetyl-o-methoxyphenoxy)-ethyl bromide, 12 g. of potassiumcarbonate and 75 ml. of l-butanol was heated at 75-78 C. -for 16 hours,cooled, filtered and the solvent evaporated. The residual oil wasdissolved in benzene and chromatographed on 200 g. of 60-100 meshmagnesium silicate, eluting which a benzene-acetone mixture. The productWeighed 4.1 g. (56% yield). The free base was dissolved in isopropanoland treated with 2.5 g. (0.02 mole) of oxalic acid dihydrate. Thecrystalline salt which formed was recrystallized twice from isopropanol.The product weighing 3.4 g. softened at 127 C. and melted at 129- 132 C.

Analysis.Calculated for C24H27NO3: C, 63.01; H, 5.95; N, 3.06. Found: C,63.01; H, 6.06; N, 3.14.

EXAMPLE 16 1-[3-(p-acetyl-o-methoxyphenoxy)propyl]-3- benzoylpyrrolidineoxalate A mixture of 3.5 g. (0.02 mole) of 3-benzoylpyrrolidine, 5.7 g.(0.02 mole) of 3-(p-acetyl-o-methoxyphenoxy)-propyl bromide, 12 g. ofpotassium carbonate and 75 ml. of toluene was refluxed for 16 hours,cooled and treated with 100 ml. of water. The organic layer was separated, washed with cold water and the solvent evaporated. The residualoil was dissolved in benzene and chromatographed on 150 g. of magnesiumsilicate, eluting with a benzene-acetone mixture. The product weighed2.0 g. (26% yield). The free base was treated with a solution of 0.7 g.(0.06 mole) of oxalic acid in isopropanol. The salt which separatedweighed 2.2 g. and melted at 114-119 C.

Analysis.Calculated for C H NO C, 63.68; H, 6.20; N, 2.97. Found: C,63.47; H, 6.13; N, 3.05.

EXAMPLE 17 1- 3- (p-fluorobenzoyl) -propyl] -3-(p-fluoro-=benzoyl)-pyrrolidine A stirred mixture of 3.8 g. (0.020 mole) of3-(pfluorobenzoyl)-pyrrolidine, 5.8 g. (0.024 mole) of 2-(3-chloropropyl)-2-(p-fluorophenyl)-l,3-dioxolane, 14.0 g.

of potassium carbonate and 75 m1. of l-butanol was heated at 80 C. for32 hours and then at reflux for 16 hours. The cooled suspension wasfiltered and the solvent evaporated at reduced pressure. The residualoil was stirred in a mixture of 100 ml. of 3 N HCl and 100 ml. ofethanol for one hour. After the mixture was made basic with 50% NaOH,the oil in which separated was extracted with benzene and the benzeneevaporated. The residual oil (6.1 g.) was chromatographed on 200 g. of60-100 mesh magnesium silicate, eluting with a benzene-acetone mixture.The product (tan wax) weighed 1.5 g. (21% yield). A portion of theproduct was molecularly distilled to obtain a pure sample.

Analysis.Calculated for C21H21F2NO21 C, H, 5.92; N, 3.92. Found: C,70.81; H, 6.10; N, 3.98.

EXAMPLE 18 fl-Aziridinylpropiophenone A solution of 35.4 gms. (0.20mole) of B-dimethylaminopropiophenone in 200 ml. of dimethylformamidewas treated with 50 gms. (1.16 mole) of aziridine and the reactionmixture was allowed to stand 48 hours at room temperature while a slowstream of nitrogen was passed through the mixture. The solution waspoured into water and the aqueous solution extracted with benzene. Thecombined benzene extracts were washed with water and dried overmagnesium sulfate. An aliquot of the benzene solution was concentratedand the residue 10 molecularly distilled at C./0.1 mm. The nuclearmagnetic resonance spectrum was consistent with the proposed structure.

EXAMPLE 19 l-carbethoxy-3-benzoylpyrrolidine (Method A) A solutioncontaining approximately 0.20 mole of B- aziridinylpropiophenone in 200ml. of dry benzene was treated dropwise at 20 C. with 18 gms. (0.17mole) of ethylchlorocarbonate to give an almost quantitative yield of ,8[N carbethoxy N (2 chloroethylamino)]- propiophenone. The course of thepreceding reaction was followed by thin layer chromatography.

The benzene solution ofS-[N-carbethoxy-N-(2-chloroethylamino)l-propiophenone was treated with4.8 gms. (0.20 mole) of sodium hydride. No reaction occurred when thebenzene solution was refluxed. Dimethylformamide was added to thebenzene solution resulting in a vigorous evolution of hydrogen gas. Thesolution after refluxing for a short period was cooled, poured intowater, the benzene layer separated, dried over magnesium sulfate andconcentrated to an oil. The oil was chromatographed on 800 gms. of 60100mesh magnesium silicate and the product eluted from the column usingbenzene-acetone solution. The infrared and nuclear magnetic spectra ofthe product was identical to that of l-carbethoxy-3-benzoylpyrrolidineprepared by Method B described in Example 20.

EXAMPLE 20 1-carbethoxy-3-benzoylpyrrolidine (Method B) To a coldstirred mixture (0 C.) of 1.5 gms. (0.008 mole) of S-benzoylpyrrolidine,2.2 gms. (0.016 mole) of potassium carbonate and 20 ml. of methylenechloride was added 0.88 gm. (0.008 mole) of ethyl chlorocarbonate.Approximately 10 gms. of ice was added to the reaction mixture which wasstirred until the pot temperature reached room temperature. The twophase system was separated and the organic layer was washed with dilutehydrochloric acid, dried over magnesium sulfate and the dried oragnicsolution concentrated to an oil. The oil was purified by chromatographyusing magnesium silicate, the pure product eluted from the column usingbenzene-acetone. The pure product weighed 1.0 gm. (50%). The materialwas molecularly distilled.

Analysis.Calculated for C14H17NO3Z C, 68.00; H, 6.93; N, 5.67. Found: C,67.93; H, 6.99; N, 5.84.

EXAMPLE 21 3-benzoylpyrrolidine hydrochloride hydrate Ten grams (0.04mole) of 3-benzoyl-1-carbethoxypyrrolidine was mixed with 25 ml. ofabsolute ethanol and 25 ml. of concentrated hydrochloric acid and thesolution refluxed for 18 hours. The cooled reaction mixture wasextracted with ether and the aqueous acid solution was concentrated toan oil. The oil was dissolved in hot acetone and from the cooled acetonesolution 5.0 gms. (63%) of the hydrochloride salt was obtained. The saltmelted at 59-61%. A mixture melting point with the compound prepared inExample 12 showed no depression.

The present invention also contemplates novel compositions containingthe compounds of the invention as active ingredients. In forming thenovel compositions of this invention, the active ingredient isincorporated in a suitable carrier, illustratively, a pharmaceuticalcarrier. Suitable pharmaceutical carriers which are useful informulating the compositions of this invention include starch, gelatin,glucose, magnesium, carbonate, lactose, malt and the like. Liquidcompositions are also within the purview of this invention and suitableliquid pharmaceutical carriers include ethyl alcohol, water, saline,propylene glycol, glycerine, glucose syrup and the like. The physicalform of the novel compositions depends in part upon the physicalcharacteristics of the active ingredient. When the active ingredient isa solid, the composition is preferably formulated as a capsule ortablet. When the active ingredient is a liquid, the composition ispreferably formulated as a soft gelatin capsule. The preferredcomposition is a tablet containing the active ingredient in the form ofits nontoxic acid-addition salt.

The following are examples of compositions formed in accordance withthis invention:

(1) CAPSULES Capsules of 5 mg., 25 mg., and 50 mg. of active ingredientper capsule are prepared. With the higher amounts of active ingredient,reduction may be made in the amount of lactose.

Typical blend for encapsulation: Per capsule, mg. Active ingredient, assalt 5.0 Lactose 296.7 Starch 129.0

Magnesium stearate 4.3

Total 435.0

Additional capsule formulations preferably contain a higher dosage ofactive ingredient and are as follows:

100 mg. per 250 mg. per 500 mg. per

Ingredients capsule capsule capsule Active ingredient, as salt- 100.250. 0 500.0 Lactose 231. 126. 5 31. 1 Starch 99. 2 54. 2 13. 4Magnesium stearate. 4. 3 4. 3 5. 5

Total 435. 0 435. 0 550. 0

In each case, uniformly blend the selected active ingredient withlactose, starch, and magnesium stearate and encapsulate the blend.

2 TABLETS A typical formulation for a tablet containing 5.0 mg. ofactive ingredient per tablet follows. The formulation may be used forother strengths of active ingredient by adjustment of weight ofdicalcium phosphate.

Per tablet, mg.

(1) Active ingredient, as salt 5.0 (2) Corn starch 13.6 (3) Corn starch(paste) 3.4 (4) Lactose 79.2 (5) Dicalcium phosphate 68.0 (6) Calciumstearate 0.9

Total 170.1

A. 50 mg. tablet Ingredients: Per tablet, mg. Active ingredient, as salt50.0 Lactose 90.0

Milo starch 20.0 Corn starch 38.0 Calcium stearate 2.0

Total 200.0

Uniformly blend the active ingredient, lactose, milo starch and the cornstarch. This blend is granulated using water as a granulating medium.The wet granules are passed through an eight mesh screen and dried at140 to 160 degrees Fahrenheit over night. The dried 12 granules arepassed through a number ten mesh screen and blended with the properamount of calcium stearate and this blend is then converted into tabletson a suitable tablet press.

B. mg. tablet Ingredients: Per tablet, mg. Active ingredient, as salt100.0 Lactose 190.0 Dicalcium phosphate 72.2 Starch 54.0 Milo starch21.6 Calcium stearate 2.2

Total 540.0

Uniformly blend the active ingredient, lactose, dicalcium phosphate,starch and milo starch. This blend is granulated with water and the wetmass is passed through a number eight mesh screen. The wet granules aredried at -160 degrees Fahrenheit over night. The dried granules arepassed through a number ten mesh screen. These dried granules areblended with the proper weight of calcium stearate and the lubricatedgranules are then converted into tablets on a suitable tablet press.

Various modifications and equivalents will be apparent to one skilled inthe art and may be made in the compounds, compositions, methods, andprocedures of the present invention without departing from the spirit orscope thereof, and it is therefore to be understood that the inventionis to be limited only by the scope of the appended claims.

What is claimed:

1. A compound selected from the group having the formula:

wherein;

R is selected from the group consisting of hydrogen,

lower alkyl, phenyllower alkyl, p-acetyl-o-methoxyphenoxyethyl,p-acetyl-o-methoxyphenoxypropyl, pfluorobenzoyl, lower cycloalkyl havingthree to nine carbon atoms inclusive, 2-ethoxyethyl,

R is selected from the group consisting of hydrogen, lower alkoxy,trifluoromethyl, halogen having an atomic weight less than 80 and loweralkyl, and acid addition salts thereof.

2. A compound of claim 1 which is 3-benzoyl-l-ethylpyrrolidine.

3. A compound of claim 1 which is 3-benzoyl-1-methylpyrrolidine.

4. A compound of claim 1 which is 3-benzoyl-1-isopropylpyrrolidine.

13 14 12. A compound of claim 1 which is 1-[3-p-acetyl-o- ReferencesCited methoxyphenoxy) -propyl] -3-benzoylpyrrolidine. UNITED STATESPATENTS 13. A compound of claim 1 which is 1-[3-(p-fluoron bemoyl)propyn 3 (p fiuorobenzoy1) pyrrolidine 3,318,908 5/1967 Sw1d1nsky et al260J26.3

14. A compound of claim 1 Which is 3-benzoylpyrrol- 5 ALEX M AZELPrimary Examiner idine.

15. A compound of claim 1 which is 3-(p-fiuoroben- TOVAR AsslstantExammer zoyl)-pyrrolidine.

16. A compound of claim 1 which is3-(m-trifluoromethyl-benzoyl)-pyrro1idine. 1O 260326.3; 424274

